The present invention relates to 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives and their addition salts effective for the therapy of disorder of cerebral nerve cells, as antagonists against excitatory amino acid receptor, in particular, selective antagonists against AMPA receptor in non-NMDA receptor, processes for preparing them, and medicinal compositions containing these compounds.
The glutamic acid being excitatory amino acid is a principal excitatory transmitter substance in the central nervous system of vertebrates, and is known as an amino acid that is contained most rich in brain. It is known, however, that, when released from the axon terminals of nerves exceeding physiological threshold, the overstimutation to the postsynaptic glutamic acid receptors causes the death of nerve cells. This is called excitotoxicity.
In recent years, it is being clarified that the excitotoxicity due to glutamic acid is concerned deeply in the various diseases of cerebral nerves such as cerebral hemorrhage, cephalic injury, epileptic intussusception, Huntington""s chorea, Parkinson""s disease, amyotrophic lateral sclerosis and Alzheimer""s disease. If such excitotoxicity can be prevented effectively, it is considered that a potential for the therapy of these intractable diseases, for which currently there is no therapeutic means whatsoever would be opened.
Classifying roughly, the glutamic acid receptor is divided into ion channel type receptor and G protein-binding type receptor, and this ion channel type receptor is further divided into NMDA (N-methyl-D-aspartic acid) receptor and non-NMDA receptor. Moreover, the latter non-NMDA receptor is classified into AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor and KA (kainic acid) receptor.
Studies on these excitatory amino acid receptors are being put forward and, above all, it is known that a drug with antagonism against AMPA receptor in non-NMDA receptor expresses no side effects (learning and memory disturbances, schizophrenia-like symptom, etc.) that are brought with a drug (MK-801 or the like) with antagonism against NMDA receptor. (Neurosci. Biobehav. Rev., 1992, 16, 13-24; J. Pharmacol. Exp. Ther., 1958, 245, 969-974), and that the protective effect on cerebral nerves can be expected even by administration after ischemia (Science, 1990, 247, 571-574).
Moreover, compounds with antagonism against AMPA receptor like NBQX having a quinoxalinedione structure have reportedly drawbacks of causing kidney disturbance, etc. that are considered to be based on the physicochemical properties (J. Cereb. Blood Flow Metab., 1994, 14, 251-261), therefore they cannot be said to be satisfactory compounds.
Now, as compounds with a structure similar to quinoxalinecarboxylic acid derivatives, compounds represented by a general formula (A) 
(wherein X independently denotes a chlorine or bromine atom, and R denotes a methyl or ethyl group), described in Japanese Unexamined Patent Publication No. Sho 56-5416 by Lilly Co. as compounds with antiviral function, compounds represented by a general formula (B) 
(wherein R and R1 independently denote halogen atoms, R2 denotes a hydrogen, methyl or ethyl group, R3 denotes a hydrogen, methyl, ethyl, hydroxyethyl, benzyl or ethoxycarbonylmethyl group, and R4 denotes a cyclooctyl, norbornyl group or the like), described in Japanese Unexamined Patent Publication No. Sho 56-81569 by Lilly Co. similarly as compounds with antiviral function, and the like are known. However, the 6 and 7 positions are symmetric in these compounds, it is not known that they have antagonism against AMPA receptor in excitatory amino acid receptor of the inventive compounds, and they have a structure different from, that of the inventive compounds.
In addition, compounds represented by a general formula 
(wherein R and R4 independently denote hydrogens, nitro or methoxy groups, R1 and R2 independently denote hydrogens, nitro or methoxy groups, or halogen atoms (one of R, R1, R2 and R4 is a group other than hydrogen, in the case of R1 and R2 being not nitro groups or methoxy groups, R1 and R2 are independently halogen atoms together and R and R4 are hydrogens, and, in the case of one of R, R1, R2 and R4 being a nitro group, either one of R1 and R2 is a methoxy group), R3 denotes a hydrogen, lower alkyl group which may be substituted with halogen, lower cycloalkyl group, lower alkenyl group or 2-chloroethyl group, and n denotes 0 or 2), described in Japanese Unexamined Patent Publication No. Sho 55-69514 by Lilly Co. similarly as compounds with antiviral function, are known, but the disclosed compounds have a structure different from that of the inventive compounds and it is not described that they have antagonism against AMPA receptor in excitatory amino acid receptor that the inventive compounds have.
Moreover, in W092-11245 described by Warner-Lambert Co., compounds represented by a general formula (D) 
(wherein Y denotes an oxygen, sulfur or nitrogen atom, R1, R2, R11 and R12 denote hydrogens, lower alkyl groups which may be substituted with halogen, halogen atoms, trifluoromethyl groups, cyano groups, nitro groups, methylthio groups, lower alkenyl groups, lower alkynyl groups, sulfonamide groups or the like, or arbitrary two of R1, R2, R11 and R12 may form a ring (6-membered ring or heterocycle which may contain heteroatom), and X denotes a sulfonylamide group which may have substituent, or the like) are known as compounds with antagonism against excitatory amino acid receptors.
However, for these compounds, those having asymmetric substituents of 6 and 7 positions of quinoxaline as the inventive compounds are not disclosed, and, with disclosed compounds, no AMPA antagonism is shown and the disclosed glycine antagonism cannot be considered to be satisfactory as well.
The invention is to provide compounds with antagonism against receptor of glutamic acid that is considered to be an etiology bringing about memory disturbance or dementia due to said diseases and selective death of cells, in particular, with high affinity and selectivity against AMPA receptor in non-NMDA receptor, and with protective effect on the cerebral nerve cells.
As a result of diligent studies exploring an antagonistic drug against excitatory amino acid receptor effective for the therapy of disorder of cerebral nerve cells, in particular, selective antagonistic drug against AMPA receptor in non-NMDA receptor, aiming at the development of novel therapeutic drug for the disorder of cerebral nerve cells, the inventors have found that the inventive 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives and their addition salts have excellent antagonism against AMPA receptor.
Namely, according to the invention, it has been found that 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by a general formula (1) 
[wherein, Q denotes a halogen atom, lower alkyl group which may be substituted with halogen atom, general formula (2)
Arxe2x80x94Pxe2x80x94xe2x80x83xe2x80x83(2)
(wherein Ar denotes a phenyl group which may have one or more substituents or naphthyl group, and P denotes a lower alkylene, lower alkenylene, lower alkynylene, oxygen or sulfur atom), general formula (3)
xe2x80x83Lxe2x80x94Axe2x80x94xe2x80x83xe2x80x83(3)
(wherein L denotes a general formula (4) 
(wherein V denotes a single bond, lower alkylene or lower alkenylene, T denotes a phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, hydroxyl group, thiol group, amino group which may be substituted, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (4-a) 
or general formula (4-b) 
(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R3 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group), or general formula (4-c) 
(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R4 and R5 identically or differently denote aralkyl groups, phenyl groups, naphthyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (these may have one or more substituents on heterocycle or condensed ring) which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1,
A denotes a single bond, lower alkylene, lower alkenylene or lower alkynylene, or general formula (5) 
xe2x80x83(wherein R6 and R7 identically or differently denote hydrogen atoms, lower alkyl groups which may be substituted with halogen atom, cycloalkyl groups, phenyl groups which may have one or more substituents or aralkyl groups which may have one or more substituents);
R1 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group,
R2 denotes a hydroxyl group, lower alkoxy group, or general formula (6) 
xe2x80x83(wherein R8 and R9 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R8 and R9 may form a ring (which may additionally contain one or two heteroatoms) together with nitrogen atom, or either of R8 and R9 denotes a hydrogen atom while the other denotes a phenyloxy group or aralkyloxy group (these may have one or more substituents on aromatic ring), hydroxyl group or lower alkoxy group), and
R denotes a nitro group, trifluoromethyl group, amino group which may be substituted, or general formula (7) 
xe2x80x83(wherein R10 and R11 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R10 and R11 may form a ring (which may additionally contain one or two heteroatoms) together with nitrogen atom, and n denotes 1 to 2)], and their addition salts have excellent antagonism against AMPA receptor, leading to the completion of the invention.
Moreover, according to the invention, it has been found that 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by a general formula (1) 
[wherein, Q denotes a halogen atom, lower alkyl group which may be substituted with halogen atom, general formula (2)
Arxe2x80x94Pxe2x80x94xe2x80x83xe2x80x83(2)
(wherein Ar denotes a phenyl group which may have one or more substituents or naphthyl group, and P denotes a lower alkylene, lower alkenylene, lower alkynylene, oxygen or sulfur atom), or general formula (5) 
(wherein R6 and R7 identically or differently denote hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, phenyl groups which may have one or more substituents or aralkyl groups which may have one or more substituents),
R denotes a nitro group, trifluoromethyl group, amino group which may be substituted, or general formula (7) 
xe2x80x83(wherein R10 and R11 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R10 and R11 may form a ring (which may additionally,contain one or two heteroatoms) together with, nitrogen atom), and n denotes 1 to 2),
R1 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R2 denotes a hydroxyl group, lower alkoxy group, or general formula (6) 
xe2x80x83(wherein R8 and R9 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R8 and R9 may form a ring (which may additionally contain one or two heteroatoms) together with nitrogen atom, or either of R8 and R9 denotes a hydrogen atom while the other denotes a phenyloxy group or aralkyloxy group (these may have one or more substituents on aromatic ring), hydroxyl group or lower alkoxy group)], and their addition salts have excellent antagonism against AMPA receptor.
Furthermore, according to the invention, it has been found that 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by a general formula (1-a) 
(wherein L denotes a general formula (4) 
(wherein V denotes a single bond, lower alkylene or lower alkenylene, T denotes a phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydroxyl group, thiol group, amino group which may be substituted, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (4-a) 
or general formula (4-b) 
(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R3 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group), or general formula (4-c) 
(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R4 and R5 identically or differently denote aralkyl groups, phenyl groups, naphthyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (these may have one or more substituents on heterocycle or condensed ring) which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1,
A denotes a single bond, lower alkylene or lower alkenylene,
R1 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and
R2 denotes a hydroxyl group, lower alkoxy group, or general formula (6) 
xe2x80x83(wherein R8 and R9 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R8 and R9 may form a ring (which may additionally contain one or two heteroatoms) together with nitrogen atom, or either of R8 and R9 denotes a hydrogen atom while the other denotes a phenyloxy group or aralkyloxy group (these may have one or more substituents on aromatic ring), hydroxyl group or lower alkoxy group)], and their addition salts have excellent antagonism against AMPA receptor.
Still more, according to the invention, it has been found that 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by a general formula (1-b) 
(wherein L denotes a general formula (4) 
(wherein V denotes a single bond, lower alkylene or lower alkenylene, T denotes a phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydroxyl group, thiol group, amino group which may be substituted, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (4-a) 
or general formula (4-b) 
(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R3 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group), or general formula (4-c) 
(wherein X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R4 and R5 identically or differently denote aralkyl groups, phenyl groups, naphthyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups), ring B denotes a saturated or unsaturated heterocycle and its condensed ring (these may have one or more substituents on heterocycle or condensed ring) which may additionally contain one or two oxygen, nitrogen or sulfur atoms, and m denotes 0 or 1,
A denotes a single bond, lower alkylene or lower alkenylene,
R denotes a nitro group, amino group which may be substituted, or general formula (7) 
xe2x80x83(wherein R10 and R11 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R10 and R11 may form a ring (which may additionally contain one or two heteroatoms) together with nitrogen atom), and n denotes 1 to 2),
R1 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and
R2 denotes a hydroxyl group, lower alkoxy group, or general formula (6) 
xe2x80x83(wherein R8 and R9 identically or differently denote aralkyl groups, phenyl groups, 5- or 6-membered heterocycles and their condensed rings (these may have one or more substituents on aromatic rings or heterocycles), hydrogen atoms, lower alkyl groups which may be substituted with halogen atom or cycloalkyl groups, or R8 and R9 may form a ring (which may additionally contain one or two heteroatoms) together with nitrogen atom, or either of R8 and R9 denotes a hydrogen atom while the other denotes a phenyloxy group or aralkyloxy group (these may have one or more substituents on aromatic ring), hydroxyl group or lower alkoxy group)], and their addition salts have excellent antagonism against AMPA receptor, leading to the completion of the invention.
In the general formula (1-a) of the inventive compounds, preferably, compounds wherein R1 is a hydrogen atom, R2 is a hydroxyl group or lower alkoxy group, A is a single bond, and, in the general formula (4) for L, V is a lower alkylene and T is general formula (4-a) or general formula (4-c) can be mentioned.
As these preferable compounds, following compounds, namely,
Ethyl 3,4-dihydro-7-(4-(hydroxymethyl)imidazole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
Ethyl 3,4-dihydro-7-(4-((N-(4-ethoxycarbonylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
Ethyl 3,4-dihydro-7-(4-(((4-ethoxycarbonyl-2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
7-(4-((N-(4-Carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid,
Ethyl 3,4-dihydro-7-(4-((N-(4-ethoxycarbonyl-2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
7-(4-((N-(4-Carboxy-2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethyl-quinoxaline-2-carboxylic acid,
Ethyl 3,4-dihydro-7-(4-((N-(4-ethoxycarbonylmethylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
7-(4-((N-(4-Carboxymethylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid,
Ethyl 3,4-dihydro-7-(4-(((4-ethoxycarbonylphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
7-(4-(((4-Carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid,
Ethyl 7-(3-formylpyrrole-1-yl)-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate,
Ethyl 7-(3-(aminomethyl)pyrrole-1-yl)-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate hydrochloride,
Ethyl 7-(3-(((4-ethoxycarbonylphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate,
Ethyl 7-(3-(((4-ethoxycarbonylphenyl-2-fluorophenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate,
Ethyl 3,4-dihydro-7-(3-(((4-ethoxycarbonylphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
7-(3-(((4-Carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid,
Ethyl 3,4-dihydro-7-(3-(((4-ethoxycarbonyl-2-fluorophenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate,
7-(3-(((4-Carboxy-2-fluorophenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid, and the like can be mentioned.
In the general formula (1-b) of the inventive compounds, preferably, compounds wherein R is nitro group, R1 is hydrogen atom, R2 is hydroxyl group, A is single bond, and, in the general formula (4) for L, V is lower alkylene and T is general formula (4-a) or general formula (4-c) can be mentioned.
As these preferable compounds, following compounds, namely,
3,4-Dihydro-6-nitro-7-(4-((N-isopropylcarbamoyloxy)methyl)imidazolyl)-3-oxo-quinoxaline-2-carboxylic acid,
7-(4-((N-n-Butylcarbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-t-Butylcarbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-6-nitro-3-oxo-7-(4-((N-phenyl-carbamoyloxy)methyl)imidazolyl)quinoxaline-2-carboxylic acid,
7-(4-((N-(4-Isopropylphenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(2-Bromophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(3-Bromophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(4-Bromophenyl)carbamoyloxy)methylbimidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(2-Chlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(3-Chlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(4-Chlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(2,3-Dichlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(2,4-Dichlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(2,5-Dichlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(2,6-Dichlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(3,4-Dichlorophenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(3,5-Dichlorophenyl)carbamnoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(4-((N-(4-methoxyphenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(4-((N-(2-fluorophenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-4--((N-(3-fluorophenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxyic acid,
3,4-Dihydro-7-(4-((N-(4-fluorophenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(4-((N-(2-methyiphenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(4-((N-(3-methylphenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(4-((N-(4-methylphenyl)carbamoyloxy)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-6-nitro-3-oxo-7-(4-((N-(2-trifluoromethylphenyl)carbamoyloxy)methyl)imidazolyl)-quinoxaline2-carboxylic acid,
3,4-Dihydro-6-nitro-3-oxo-7-(4-((N-(3-trifluoromethylphenyl)carbamoyloxy)methyl)imidazolyl)quinoxaline-2-carboxylic acid,
3,4-Dihydro-6-nitro-3-oxo-7-(4-((N-(4-trifluoromethylphenyl)carbamoyloxy)methyl)imidazolyl)quinoxaline-2-carboxylic acid,
3,4-Dihydro-6-nitro-3-oxo-7-(4-((N-(4-trifluoromethoxyphenyl)carbamoyloxy)methyl)imidazolyl)quinoxaline-2-carboxylic acid,
7-(4-((N-(3-Carboxyphenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-((N-(4-Carboxyphenyl)carbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(4-(((2-fluorophenyl)aminocarbonylamino)methyl)imidazolyl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(4-(((4-Carboxyphenyl)aminocarbonylamino)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
Sodium 7-(4-((N-benzylcarbamoyloxy)methyl)imidazolyl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylate,
3,4-Dihydro-6-nitro-3-oxo-7-(3-((N-phenylcarbamoyloxy)methyl)-4-pyridone-1-yl)quinoxaline-2-carboxylic acid,
7-(3-((N-(2-Bromophenyl)carbamoyloxy)methyl)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((N-(3-Bromophenyl)carbamoyloxy)methyl)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((N-(4-Bromophenyl)carbamoyloxy)methyl)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((N-(3-Carboxyphenyl)carbamoyloxy)methyl)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-6-nitro-3-oxo-7-(3-(phenylaminocarbonylamino)-4-pyridone-1-yl)quinoxaline-2-carboxylic acid,
7-(3-((2-Bromophenyl)aminocarbonylamino)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((3-Bromophenyl)aminocarbonylamino)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((4-Bromophenyl)aminocarbonylamino)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(3-((4-fluorophenyl)aminocarbonylamino)-4-pyridone-1-yl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(3-((4-methylphenyl)aminocarbonylamino)-4-pyridone-1-yl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
3,4-Dihydro-7-(3-((4-methoxyphenyl)aminocarbonylamino)-4-pyridone-1-yl)-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-(Benzylaminocarbonylamino)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((4-Bromobenzyl)carbonylamino)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
7-(3-((4-Bromophenyl)carbonylamino)-4-pyridone-1-yl)-3,4-dihydro-6-nitro-3-oxoquinoxaline-2-carboxylic acid,
Ethyl 3-ethoxy-7-(4-(hydroxymethyl)imidazolyl)-6-nitroquinoxaline-2-carboxylate,
Ethyl 7-(4-((N-(4-bromophenyl)carbamoyloxy)methyl)imidazolyl)-3-ethoxy-6-nitroquinoxaline-2-carboxylate,
Ethyl 3-ethoxy-6-nitro-7-(4-(trifluoroacetamidomethyl)imidazolyl)quinoxaline-2-carboxylate,
Ethyl 3-ethoxy-7-(3-(hydroxymethyl)-4-pyridone-1-yl)-6-nitroquinoxaline-2-carboxylate,
Ethyl 7-(3-amino-4-pyridone-1-yl)-3-ethoxy-6-nitroquinoxaline-2-carboxylate,
Ethyl 7-(3-((4-bromophenyl)aminocarbonylamino)-4-pyridone-1-yl)-3-ethoxy-6-nitroquinoxaline-2-carboxylate, and the like can be mentioned.
In the description of the general formula (1) of the invention, for the substituents in the phrases of xe2x80x9cphenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, xe2x80x9caralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, xe2x80x9cring B denotes a saturated or unsaturated heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle) which may additionally contain one or two oxygen, nitrogen or sulfur atomsxe2x80x9d, xe2x80x9caralkyl group, phenyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, xe2x80x9cphenyloxy group, aralkyloxy group (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, xe2x80x9cphenyl group which may have one or more substituents or aralkyl group which may have one or more substituentsxe2x80x9d, and xe2x80x9cphenyl group which may have one or more substituents or naphthyl groupxe2x80x9d, halogen atom, hydroxyl group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group, lower alkylthio group, lower alkoxycarbonyl group, nitro group, amino group, cyano group, carboxyl group, aldehyde group, lower alkyl group with carboxyl group or the like are mentioned, for xe2x80x9clower alkyl groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, n-propyl, iso-propyl or the like are mentioned, for xe2x80x9ccycloalkyl groupsxe2x80x9d, ones with carbon atoms of 3 to 7 such as cyclopropyl, cyclopentyl, cyclohexyl or the like are mentioned, for xe2x80x9chalogen atomsxe2x80x9d, fluorine, chlorine, bromine and iodine are mentioned, for xe2x80x9clower alkoxy groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 tod 4 such as methoxy, ethoxy, propoxy or the like are mentioned, for xe2x80x9clower alkylthio groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methylthio, ethylthio, propylthio or the like are mentioned, for xe2x80x9clower alkoxycarbonyl groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methoxycarbonyl, ethoxycarbonyl or the like are mentioned, for xe2x80x9caralkyloxy groupsxe2x80x9d, benzyloxy, phenylethyloxy, phenylpropyloxy or the like are mentioned, for xe2x80x9caralkylthio groupsxe2x80x9d, benzylthio, phenylethylthio, phenylpropylthio or the like are mentioned, and, for xe2x80x9camino groups which may be substitutedxe2x80x9d, amino groups which may be substituted with acyl group or arylsulfonyl group, for example, acetyl, methanesulfonyl, phenylsulfonyl or the like, or which may be substituted with lower alkyl group which may be substituted with one or two halogen atoms, phenyl group which may have one or two substituents and aralkyl group which may have one or two substituents are mentioned.
The substituents referring to so here indicate xe2x80x9csubstituentsxe2x80x9d as defined above.
Further, in the description, xe2x80x9cheterocyclesxe2x80x9d in the phrases of xe2x80x9cphenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, xe2x80x9caralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), and xe2x80x9caralkyl group, phenyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, are saturated or unsaturated monocyclic or polycyclic heterocycle groups which may have one or more substituents and which can contain one or two oxygen, nitrogen or sulfur atoms, and, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl or the like are mentioned, and xe2x80x9ctheir condensed ringsxe2x80x9d represent condensed rings of said xe2x80x9cheterocyclesxe2x80x9d with benzene and, for example, indolyl, tetrahydroquinolyl, benzoxazolidinyl, benzothiazolidinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl or the like are mentioned. Moreover, for xe2x80x9cring B denotes a saturated or unsaturated heterocycle and its condensed ring which may additionally contain one or two oxygen, nitrogen or sulfur atomsxe2x80x9d, said xe2x80x9cheterocyclesxe2x80x9d and xe2x80x9ctheir condensed ringsxe2x80x9d are mentioned, further they represent saturated or unsaturated heterocycles or their condensed rings which may be substituted with carbonyl group, in which carbonyl group may be substituted onto said xe2x80x9cheterocyclesxe2x80x9d and xe2x80x9ctheir condensed ringsxe2x80x9d, and for example, 2-pyrrolidone, 3-pyrrolidone, 2-imidazolidinone, 2-thiazolidinone, 4-thiazolidinone, 2-oxazolidinone, 4-oxazolidinone, 2-pyridone, 4-pyridone, 2-pyrimidinone, 4-pyrimidinone, 2,4-pyrimidinedione, 2-quinolone, 4-quinolone, etc. are mentioned. Moreover, xe2x80x9crings (which may additionally contain one or two heteroatoms) may be formed together with nitrogen atomxe2x80x9d are saturated monocyclic or polycyclic heterocycle groups which may additionally contain one or two nitrogen, oxygen or sulfur atoms, and, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, indolyl, tetrahydroquinolyl, etc. are mentioned.
The compounds of the invention can be prepared through, for example, processes shown below.
Compounds, R1 being hydrogen atom, among the compounds represented by the general formula (1) can be synthesized by reacting compounds represented by a general formula (10) 
(wherein Q, R and R2 are as described above, and R12 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have one or more substituents), for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like.
Moreover, compounds, R1 being hydrogen atom, among the compounds represented by the general formula (1) can also be synthesized, in the case of R2 being lower alkoxy group among the compounds represented by the general formula (10) 
(wherein Q, R, R2 and R12 are as described above), by reacting those compounds for 0.5 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, lithium hydroxide or the like to convert to carboxylic acid, and then by reacting for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like.
Moreover, compounds, R1 being hydrogen atom, among the compounds represented by the general formula (1) can also be synthesized, in the case of R2 being lower alkoxy group among the compounds represented by the general formula (10) 
(wherein Q, R, R2 and R12 are as described above), by reacting those compounds for 3 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like to convert to amide-ester form, and then by reacting for 0.5 to 10 hours at 20 to 100xc2x0 C. in a solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide or the like.
Moreover, when converting compounds, R2 being lower alkoxy group, to compounds, R2 being hydroxyl group, among the compounds represented by the general formula (1), the latter compounds can also be synthesized by reacting the former compounds for 0.5 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, lithium hydroxide or the like.
Moreover, compounds, R1 being hydrogen atom, among the compounds represented by the general formula (1) can also be converted to compounds, R1 being substituted with lower alkyl group, aralkyl group (which may have one or more substituents) or cyclic alkyl group, by reacting with alkyl halide, for example, methyl iodide or the like, aralkyl halide, for example, benzyl chloride, 4-methoxybenzyl chloride or the like or cyclic alkyl halide, for example, cyclopentyl bromide, cyclohexyl bromide or the like for 2 to 10 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or the like, using a suitable base, for example, sodium hydride, sodium carbonate, potassium carbonate or the like.
Moreover, compounds represented by the general formula (1) can be synthesized by reacting compounds represented by a general formula (11) 
(wherein Q, R, R1 and R2 are as described above), for 1 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, using an oxidizing agent, for example, DDQ (dichlorodicyanoquinone).
Moreover, compounds represented by the general formula (1) can also be synthesized by reacting compounds represented by the general formula (11) for 1 to 72 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, ethanol, toluene or the like, using a suitable base, for example, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate or the like.
Moreover, compounds, L being general formula (4) and, for T, W in the general formula (4-a) and general formula (4-c) being aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle or its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), among the compounds, Q in the general formula (1) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (12) 
(wherein La is general formula (13) 
(wherein T1 denotes a hydroxyl group, thiol group or amino group which may be substituted, and A, R, R1, R2, ring B, V and m are as described above), with compounds represented by a general formula (14)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(14)
(wherein Z denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cyclic alkyl group, and Xa denotes an oxygen or sulfur atom), for 0.5 to 15 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, methylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like.
Also, they can be synthesized by converting compounds represented by a general formula (15)
Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(15)
(wherein Z denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cyclic alkyl group, A1 denotes a single bond, lower alkylene, lower alkenylene or lower alkynylene, and D denotes an amino group, carboxyl group, amide group or lower alkoxycarbonyl group), in place of general formula (14), to isocyanic (isothiocyanic) ester or carbamoyl chloride through known process, and by reacting with general formula (12) similarly to general formula (14).
For example, in the case of D being amino group, they can be converted to carbamoyl chloride or isocyanic (isothiocyanic) ester by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homolog (4-nitrophenyl chloroformate or the like) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like.
Further, they can be converted to isocyanic ester by changing carboxyl group to acid azide and then using Crutius rearrangement or Schmidt rearrangement in the case of D being carboxyl group, and using Hofmann rearrangement in the case of D being amide group. Moreover, in the case of D being carboxyl group, they can also be converted to isocyanic ester in one pot, using DPPA (diphenylphosphoryl azide).
Moreover, compounds, L being general formula (4), among the compounds, Q in the general formula (1) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (16) 
(wherein A, R, R1 and R2 are as described above), with compounds represented by a general formula (17) 
(wherein T, V, and m are as described above, and R13 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have one or more substituents), for 0.5 to 5 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, benzene, toluene, acetic acid or the like, using a suitable inorganic or organic acid, for example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or the like.
Moreover, compounds, L being general formula (4), among the compounds, Q in the general formula (1) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (20) 
(wherein R and R2 are as described above, and Xb denotes a halogen atom), or compounds represented by a general formula (20-a) 
(wherein R, R2 and Xb are as described above, and R1 denotes a lower alkyl group or aralkyl group which may have one or more substituents), which are obtained by reacting that general formula (20) with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride or the like for 2 to 10 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or the like, using a suitable base, for example, sodium hydride, sodium carbonate, potassium carbonate or the like, with compounds represented by a general formula (19) 
(wherein T, V, ring B and m are as described above) for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, Q in the general formula (1) being general formula (2) or general formula (5), can also be synthesized by reacting compounds represented by the general formula (20) 
(wherein R, R2 and Xb are as described above), or compounds represented by the general formula (20-a) 
(wherein R, R1, R2 and Xb are as described above), which are obtained by reacting that general formula (20) with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride or the like for 2 to 10 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or the like, using a suitable base, for example, sodium hydride, sodium carbonate, potassium carbonate or the like, with compounds represented by a general formula (13-a)
Arxe2x80x94Pxe2x80x94Hxe2x80x83xe2x80x83(13-a)
(wherein Ar and P are as described above), or a general formula (13-b) 
(wherein R6 and R7 are as described above), for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, L being general formula (4) and A being lower alkylene, among the compounds, Q in the general formula (1) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (18) 
(wherein R, R1 and R2 are as described above, and E denotes a halogen atom), with compounds represented by a general formula (19) 
(wherein T, V, ring B and m are as described above), for 0.5 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, A being lower alkylene, among the compounds, Q in the general formula (1) being represented by the general formula (2) or general formula (5), can also be synthesized by reacting compounds represented by a general formula (18) 
(wherein R, R1, R2 and E are as described above), with compounds represented by he general formula (13-a)
Arxe2x80x94Pxe2x80x94Hxe2x80x83xe2x80x83(13-a)
(wherein Ar and P are as described above), or the general formula (13-b) 
(wherein R6 and R7 are as described above), for 1 to 24 hours at 25 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, N,N-dimethylformamide, benzene, toluene or the like, using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds represented by the general formula (1) or general formula (12) can also be synthesized by reacting compounds represented by a general formula (21) 
(wherein Q and R are as described above), with ketomalonic acid diester represented by a general formula (22) 
(wherein R14 denotes a lower alkyl group), for 2 to 12 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like.
Moreover, compounds, L being general formula (4) and, for T. W in the general formula (4-a) and general formula (4-c) being aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle or its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), among the compounds, Q in the general formula (10) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (23) 
(wherein La, A, R, R2 and R12 are as described above), with compounds represented by the general formula (14)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(14)
(wherein Z and Xa are as described above), for 1 to 15 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, methylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine, pyridine or the like.
Also, they can be synthesized by converting compounds represented by the general formula (15)
Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(15)
(wherein Z, A1, and D are as described above), in place of general formula (14), to isocyanic (isothiocyanic) ester or carbamoyl chloride through known process, and by reacting with general formula (23) similarly to general formula (14).
For example, in the case of D being amino group, they can be converted to carbamoyl chloride or isocyanic (isothiocyanic) ester by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homolog (4-nitrophenyl chloroformate or the like) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like.
Further, they can be converted to isocyanic ester by changing carboxyl group to acid azide and then using Crutius rearrangement or Schmidt rearrangement in the case of D being carboxyl group, and using Hofmann rearrangement in the case of D being amide group. Moreover, in the case of D being carboxyl group, they can also be converted to isocyanic ester in one pot, using DPPA (diphenylphosphoryl azide).
Moreover, compounds, L being general formula (4), among the compounds, Q in the general formula (10) being represented by the general formula (3), can be synthesized by reacting compounds represented by a general formula (24) 
(wherein R, R2, R12 and Xb are as described above), with compounds represented by the general formula (19) 
(wherein T, V ring B and m are as described above), for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, Q in the general formula (10) being represented by the general formula (2) or general formula (5), can also be synthesized by reacting compounds represented by the general formula (24) 
(wherein R, R2, R12 and Xb are as described above), with compounds represented by the general formula (13-a)
Arxe2x80x94Pxe2x80x94Hxe2x80x83xe2x80x83(13-a)
(wherein Ar and P are as described above), or the general formula (13-b) 
(wherein R6 and R7 are as described above), for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, L being general formula (4) and A being lower alkylene, among the compounds, Q in the general formula (10) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (25) 
(wherein R, R2, R12 and E are as described above), with compounds represented by the general formula (19) 
(wherein T, V, ring B and m are as described above), for 0.5 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, A being lower alkylene, among the compounds, Q in the general formula (10) being represented by the general formula (2) or general formula (5), can also be synthesized by reacting compounds represented by a general formula (25) 
(wherein R, R2, R12 and E are as described above), with compounds represented by the general formula (13-a)
Arxe2x80x94Pxe2x80x94Hxe2x80x83xe2x80x83(13-a)
(wherein Ar and P are as described above), or the general formula (13-b) 
(wherein R6 and R7 are as described above), for 1 to 24 hours at 25 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, N,N-dimethylformamide, benzene, toluene or the like, using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, represented by the general formula (24) can be synthesized by reacting compounds represented by the general formula (20) 
(wherein R, R2 and Xb are as described above), with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride or the like for 2 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable silver catalyst, for example, silver oxide, silver carbonate or the like.
Also, they can be synthesized by reacting compounds represented by the general formula (20) for 2 to 6 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a borate, for example, tetramethyloxonium borate or the like.
Moreover, compounds R being nitro group, among the compounds represented by the general formula (20) can be synthesized by selective nitration, that is, reacting compounds represented by a general formula (26) 
(wherein Xb and R2 are as described above), for 0.5 to 5 hours at xe2x88x9210 to 80xc2x0 C. in an acetic acid solvent, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate or the like.
Moreover, compounds represented by the general formula (20) can also be synthesized by reacting compounds represented by a general formula (27) 
(wherein Xb and R are as described above), with ketomalonic acid diester represented by the general formula (22) 
(wherein R14 is as described above), for 2 to 12 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like.
Part of these compounds represented by the general formula (27) is known, and can be synthesized according to usual process.
Moreover, compounds represented by the general formula (20) can also be synthesized according to WO92-11245, Japanese Unexamined Patent Publication No. Sho 56-81569 or the like which shows following scheme. 
(wherein Xb and R are as described above, and R15 denotes a lower alkyl group).
Moreover, compounds, represented by the general formula (26) can also be synthesized by reacting compounds represented by a general formula (31) 
(wherein Xb is as described above), with ketomalonic acid diester represented by the general formula (22) 
(wherein R14 is as described above), for 2 to 12 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like.
Also, part of the compounds represented by the general formula (26) is known, and can also be synthesized according to WO92-11245, Japanese Unexamined Patent Publication No. Sho 56-81569 or the like which shows following scheme. 
(wherein Xb and R15 are as described above).
Moreover, compounds, L being general formula (4), among the compounds, Q in the general formula (11) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (35) 
(wherein A, R1 and R2 are as described above), with compounds represented by the general formula (17) 
(wherein T, V, R13 and m are as described above), for 5 to 48 hours at 20 to 80xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, benzene, toluene, acetic acid or the like (to which suitable inorganic or organic acid, for example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or the like may be added).
Moreover, compounds, L being general formula (4) and, for T, W in the general formula (4-a) and general formula (4-c) being aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle or its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), among the compounds, Q in the general formula (11) being represented by the general formula (3), can also be synthesized by reacting compounds represented by a general formula (36) 
(wherein La, A, R, R1 and R2 are as described above), with compounds represented by the general formula (14)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(14xe2x80x2)
(wherein Z and Xa are as described above), for 1 to 15 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, methylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like.
Also, they can be synthesized by converting compounds represented by the general formula (15)
xe2x80x83Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(15)
(wherein Z, A1 and D are as described above), in place of general formula (14), to isocyanic (isothiocyanic) ester or carbamyl chloride through known process, and by reacting with general formula (36) similarly to general formula (14).
For example, in the case of D being amino group, they can be converted to carbamoyl chloride or isocyanic (isothiocyanic) ester by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homolog (4-nitrophenyl chloroformate or the like) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like.
Further, they can be converted to isocyanic ester by changing carboxyl group to acid azide and then using Crutius rearrangement or Schmidt rearrangement in the case of D being carboxyl group, and using Hofmann rearrangement in the case of D being amide group. Moreover, in the case of D being carboxyl group, they can also be converted to isocyanic ester in one pot, using DPPA (diphenylphosphoryl azide).
Moreover, compounds, R being trifluoromethyl group, among the compounds represented by the general formula (11) can be synthesized by reducing compounds represented by the general formula (1) through catalytic hydrogenation, that is, by hydrogenating at 20 to 80xc2x0 C. and ambient pressure to 5 atm in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium carbon, platinum oxide, rhodium-alumina or the like.
Moreover, compounds, R1 being hydrogen atom, among the compounds represented by the general formula (16) can be synthesized by reacting compounds represented by a general formula (37) 
(wherein R, R2, R12 and A are as described above, and R16 and R17 identically or differently denote hydrogen atoms, protective groups of amino group), for 3 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like.
Moreover, compounds, R2 being hydroxyl group, among the compounds represented by the general formula (16) can also be synthesized by reacting compounds represented by a general formula (38) 
(wherein R, R1, R2, A, R16 and R17 are as described above), for 0.5 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide or the like to convert to carboxylic acid, and then by reacting for 3 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like.
Here, compounds, A being single bond or lower alkylene, among the compounds represented by the general formula (37) can be synthesized by reacting compounds represented by the general formula (24) 
(wherein R, R2, R12 and Xb are as described above), or compounds represented by the general formula (25) 
(wherein R, R2, R12 and E are as described above), with compounds represented by a general formula (39)
R16R17xe2x80x94NHxe2x80x83xe2x80x83(39)
(wherein R16 and R17 are as described above), for 0.5 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds represented by the general formula (25) can be synthesized by reacting compounds represented by a general formula (40) 
(wherein R, R2 and R12 are as described above), for 1 to 12 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, carbon tetrachloride, chloroform, acetic acid or the like, using a halogenating agent, for example, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine or the like.
Moreover, compounds, A being lower alkylene, among the compounds represented by the general formula (38) can be synthesized by reacting compounds represented by the general formula (18) 
(wherein R, R1, R2 and E are as described above), with compounds represented by the general formula (39)
R16R17xe2x80x94NHxe2x80x83xe2x80x83(39)
(wherein R16 and R17 are as described above), for 5 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds represented by the general formula (18) can be synthesized by reacting compounds represented by a general formula (41) 
(wherein R, R1 and R2 are as described above), for 1 to 12 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, carbon tetrachloride, chloroform, acetic acid or the like, using a halogenating agent, for example, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine or the like.
Moreover, compound (42), R being trifluoromethyl group, R1 being hydrogen atom and A being single bond, among the compounds represented by the general formula (35) can be synthesized through a process shown in following scheme. 
It can be synthesized by reacting compound (43) synthesizable through known process with ketomalonic acid diester (22) for 1 to 6 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like to convert to compound (44), then nitrating this compound, that is, reacting for 0.5 to 6 hours at xe2x88x9210 to 80xc2x0 C. without solvent or in a suitable solvent, for example, concentrated sulfuric acid, carbon disulfide or acetic acid, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate or the like to convert to compound represented by compound (45), and reducing this through catalytic hydrogenation, that is, hydrogenating at 20 to 80xc2x0 C. under atmospheric pressure to 5 atm in a suitable solvent, for example, ethanol, methanol, acetic acid, dilute hydrochloric acid or mixed solvent thereof in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium-alumina or the like. 
(wherein R12 is as described above).
Also, compound (42) can be synthesized via compound (45a) and compound (45b), after nitration.
Namely, it can be synthesized also by reacting compound (45) with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride for 2 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable silver catalyst, for example, silver oxide, silver carbonate or the like to convert to compound (45a), then reducing this through catalytic hydrogenation, that is, hydrogenating at 20 to 80xc2x0 C. under atmospheric pressure to 5 atm in a suitable solvent, for example, ethanol, methanol, acetic acid, dilute hydrochloric acid or mixed solvent thereof in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium-alumina or the like to convert to compound (45b), and further reacting this (45b) for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like.
Also, compounds represented by the general formula (45a) can be synthesized by reacting compounds represented by the general formula (45) for 2 to 6 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a borate, for example, tetramethyloxonium borate or the like.
Moreover, compounds represented by the general formula (21) can be synthesized by reacting, for example, compounds represented by a general formula (46) 
(wherein Xb and R are as described above, and P1 and P2 denote hydrogen atoms or protective groups of amino group), with compounds represented by the general formula (19) 
(wherein T, V, ring B and m are as described above), to convert to compounds represented by a general formula (47), deprotecting these (general formula 48), and then reducing nitro group, leading to phenylenediamine (general formula 21). 
(wherein Q, R, P1 and P2 are as described above).
The reaction of general formula (46) and general formula (19) can be achieved by reacting for 5 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
The deprotection of the general formula (47) can be conducted by reacting for 3 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, methanol, ethanol, anisole or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like, or for 0.5 to 10 hours at 20 to 100xc2x0 C., using a suitable alkali, for example, potassium hydroxide, sodium hydroxide, or the like.
The reduction of nitro group of the general formula (48) can be conducted by reacting at 20 to 60xc2x0 C. in water-alcohol, for example, water-ethanol, water-methanol or the like in the presence of sodium sulfide and ammonium chloride in the case of R being nitro group. Further, in the case of R being other than nitro group, it can also be conducted by reducing through catalytic hydrogenation, that is, hydrogenating at 25 to 80xc2x0 C. under atmospheric pressure to 5 atm in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium carbon, platinum oxide, rhodium-alumina or the like. Furthermore, it can also be conducted by reacting at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, dilute hydrochloric acid, acetic acid or mixed solvent thereof in the presence of tin chloride, zinc, iron, sodium hydrosulfite or the like.
Moreover, compounds, R being trifluoromethyl group, among the compounds represented by the general formula (46) can be synthesized by nitrating general formula (50) synthesizable through known process, that is, 
(wherein Xb, P1 and P2 are as described above), by reacting for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. without solvent or in a suitable solvent, for example, concentrated sulfuric acid, carbon disulfide or acetic acid, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate or the like.
Moreover, compounds represented by the general formula (48) can also be converted to general formula (1) according to WO92-11245. Namely, nitroaniline represented by the general formula (48) can be reacted with malonyl chloride to convert to general formula (51), and then intramolecularly cyclizing to convert to general formula (52), which is deoxidated to convert to general formula (1). 
(wherein Q, R and R15 are as described above). Best embodiment to put the invention into practice